Intervention of Prostate Cancer by a Flavonoid Antioxidant Silymarin

摘要

Recently we showed that flavonoid antioxidant silymarin inhibits ERBBl activation followed by a G1 arrest and inhibition of PCA cell growth. In this grant we proposed studies to define cause and effect relationship for this effect at membrane cytoplasmic and nuclear levels, and define in vivo effect of silymarin on PCA tumor growth in nude mice. Treatment of LNCaP and DUl45 human prostate carcinoma cells with silibinin (the pure form of silymarin) resulted in strong inhibition of ligand binding to erbBl receptor and ligand internalization, and inhibition of erbBl activation followed by dimerization. These inhibitory effects of silibinin also corroborate with its inhibitory effect on both cellular and released expression of TGFalpha in these two cell lines. In cytoplasmic signaling, silibinin showed strong decrease in ERKl/2 phosphorylation in both LNCaP and DUl45 cells and inhibition in their growth. In nuclear signaling, silibinin showed strong increase in hyperphosphorylation of RB (in LNCaP) and related proteins (in DUl45) with changes in E2F family of transcription factors. These alterations were identified to be due to modulation of cell cycle regulators such as CDKIs, CDKs and cyclin. Silibinin showed strong G1 arrest, and caused differentiation of both LNCaP and DU145 cells. In one pilot studies completed silymarin feeding to nude mice showed 80% inhibition of DUl45 tumor weight. Other studies also standardized both LNCaP and DUI45 xenograft growth in nude mice, and PCNA and TUNEL staining in tumor samples. Our results suggest that silibinin could afford prevention/ intervention of human prostate cancer.